Black became a well-known actress after her role as Karen in Easy Rider (1969). She has over 100 film performances to her credit, including her role as a kidnapping accomplice in the final film Alfred Hitchcock directed, Family Plot (1976), and her turn as Rayette Dipesto in Five Easy Pieces (1970), for which she received an Academy Award nomination for Best Supporting Actress. She won a Golden Globe for Best Supporting Actress for Five Easy Pieces as well as a Golden Globe for Best Supporting Actress - Motion Picture for her role as Myrtle Wilson in The Great Gatsby (1974).
She was also nominated for Best Motion Picture Actress - Drama for her role as Faye Greener in The Day of the Locust (1975). She starred in Airport 1975 as Chief Cabin Attendant Nancy Pryor with a memorable line: "There's no one left to fly the plane!"
Black was nominated for a Grammy Award for Album of Best Original Score Written for a Motion Picture or Television Series for the film Nashville (1975). She had previously written and sang the theme song and supporting songs for The Pyx (1973). She starred in the Dan Curtis horror film about a haunted house, Burnt Offerings (1976), which featured Bette Davis in one of her final roles. She then appeared in a dual role in a 1977 thriller The Strange Possession of Mrs. Oliver.
In March 2005, Black received the Best Actress Award at the Fantasporto International Film Festival in Porto, Portugal, for her work in the critically-acclaimed Steve Balderson film Firecracker (2005), in which she plays two roles, Sandra and Eleanor. She and actor John Hurt were both presented with Career Achievement Awards as well.
Black launched a career as a playwright in May 2007 with the opening of Missouri Waltz at the Blank Theater in Los Angeles; Black stars in the play as well. Conceived as a play with music, rather than a musical, the play contains songs by Harriet Schock. The play is a bittersweet comedy about two ghosts who haunt their ancestral home in New Madrid, Missouri.
In the Family Guy episode "Death is a Bitch" Karen Black is forced to land a plane, prompting news anchor Tom Tucker to report, "Karen Black, what an obscure reference".
The Voluptuous Horror of Karen Black is a glam/punk band led by Kembra Pfahler. Guitarist Abby Normal, featured a song titled "Scream Karen Black" on his solo project album Midnight Creature Feature Picture Show.
Her likeness appears in the The Simpsons Tree House of Horror Dead Man's Jest comic book.